The type 3 secretion system (T3SS) is a multi-protein complex that plays a central role in the virulence of many bacteria categorized as Gram-negative. Gram-negative bacteria include some of the most harmful bacteria to humans and plants. T3SS directs the secretion and transfer of bacterial proteins into the cytoplasm – the portion of the cell outside the nucleus of eukaryotic cells. It’s known that the secretion system is composed of about 20 to 25 different proteins arranged into two distinct parts called the needle complex and the translocon. However, the exact mechanisms of how proteins are secreted by T3SS and the precise molecular organization of the complex are poorly understood. Dr. Neta Wexler Sal-Man aims to define, at the molecular level, the interactions of proteins that create the secretion apparatus of two pathogenic bacteria: Enteropathogenic E. coli and enterohemorrhagic E. coli. In the long term, she hopes to identify a way to manipulate the secretion system in order to inject desired proteins or molecules into eukaryotic cells. The research will help improve understanding of this highly complex type 3 secretion system and could ultimately contribute to the design of new therapeutic drugs aimed at the potentially deadly bacteria that use T3SS.
Year: 2007
Defining the role of FOXP3 in human CD4+ T cells
In recent years, new immunosuppressive drugs have made considerable improvements to the success of transplantation procedure and the treatment of autoimmune diseases. Despite these successes, the side effects of long-term drug treatment invariably decrease patients’ quality of life and cause generalized suppression of the immune system. To develop a more direct approach for these therapies, efforts are now focused on a particular aspect of the immune system that controls the response. T regulatory (Tr) cells are a subset of white blood cells that have the ability to suppress undesired immune responses, while leaving other aspects of the normal immune system intact. A gene named FoxP3 has been identified as the master controller for development of a subset of Tr cells that can provide protection against some types of autoimmune diseases and promote acceptance of foreign tissue in a transplant setting. FoxP3 plays an essential role in maintaining normal immune function, but the exact mechanisms by which this gene operates in Tr cells are not known. Due to the high potential for using Tr cells for immunomodulatory therapies, Sarah Allan is investigating the role of FoxP3 in human cells. Her research will increase our understanding of how Tr cells arise naturally, the mechanisms by which they suppress immune responses and how they differ from other types of T cells at the molecular and genetic level. This work will contribute to the development of novel therapies for autoimmune diseases, transplantation, and other pathologies of the immune system.
The structure and process level determinants of improved clinical outcomes in prehospital cardiac arrest and major trauma
Emergency Medical Services (EMS) systems provide care to complex patients under less than ideal circumstances. Paramedics treat patients without knowing much about the patient’s medical history or the cause of the emergency. This makes it very difficult to know how to evaluate the care provided to them. Generally, quality of care in medicine is evaluated by measuring the effect of various components of the system and the interaction between the clinician and the patient, to see the effect on the patient’s health. EMS managers evaluate factors such as the number of ambulances per population, the level of training of paramedics and 911 call response times. Recent research has called into question the theoretical relationship between improved quality of care and the level of training for paramedics, leaving EMS system managers with the difficult task of re-evaluating their assumptions about how to improve the quality of their systems. Douglas Andrusiek’s research will help managers by exploring the relationships between each component of the Emergency Medical System. He will conduct a statistical analysis to determine which structural and care components contribute to better patient care. While most research evaluates only cardiac arrest performance, this project is also examining EMS care of major trauma patients. Andrusiek’s research will lead to the development of strategies that will improve patient care for all British Columbians who suffer acute injury and illness.
Mechanisms for selectivity of vascular-disrupting anti-cancer therapies
Solid cancers rely on blood vessels for delivering the oxygen and nutrients that allow them to grow and metastasize (spread to other parts of the body). Chemotherapy treatment also relies on the vessels for effectively delivering anti-cancer drugs to the tumour cells. When blood vessels have abnormal features, such as in cancerous tumours, the tumours appear to be more resistant to conventional chemotherapies as the result of this abnormal vasculature. A new focus in cancer research attempts to exploit vessel abnormalities that are specific to cancer by using them as cancer therapy targets. A new class of anti-cancer drugs currently under development and in clinical trials targets the blood vessels that supply tumours in two ways: vascular targeting agents (VTAs) damage the existing blood vessels that supply tumours, while anti-angiogenic agents (AAAs) inhibit the growth of new vessels. Although VTAs cause catastrophic damage to blood vessels in the centre of tumours, they leave a rim of viable cells and vessels at the periphery that survive to regrow the tumour; AAAs are also only effective on select populations of vessels within a tumour. Jennifer Baker is studying whether vascular targeting and angiogenic agents will work more effectively in combination with eachother or with other conventional chemotherapies to stifle this subsequent tumour growth. Baker is examining which blood vessels are sensitive or resistant to the drugs, what damage the drugs cause, and how this damage affects tumour growth. The findings could result in more effective combined treatments that are capable of cutting off the blood supply to cancerous tumours, thereby preventing the tumour from growing and metastasizing.
Molecular Epidemiology of Gastric and Esophageal Cancer Survival
Cancers of stomach and esophagus (the tube from the mouth to the stomach) are a major cause of illness and death. Worldwide, the incidence of tumours at the stomach-esophagus border is increasing more rapidly than any other type of cancer. Historically, gastric and esophageal cancers have been studied separately; however, recent evidence suggests these cancers have a lot in common. As a result, studying these cancers together may result in information about the origin or effective treatment of one cancer having similar implications for the other. Morteza Bashash is investigating whether certain genes are associated with the disease progression of these cancers. Specifically, he is testing whether these patients have alteration of two groups of genes that are associated with cancer progression, Matrix Metalloproteinase (MMP) and Tissue Inhibitors of Metalloproteinase (TIMP). He is monitoring newly-diagnosed patients to determine whether the progression of the disease depends on these genes or other possible determinants such as family history, and/or the patients’ ethnicity. He is also assessing whether the effects are different in geographic areas where the cancers are becoming more common (BC), and areas where the cancers are already common. The results from this research could help identify high risk patients and provide them with more effective treatment.
Identification of Predictive Drug Response Signatures and Novel Resistance Genes by Whole Genome Profiling of Lung Tumors
Lung cancer causes more than a quarter of cancer deaths in Canada, with five-year survival rates among the lowest for commonly diagnosed cancers. Non-small cell lung cancer accounts for about 80 per cent of all lung tumours. Unfortunately, many cases are inoperable by the time they’re diagnosed, leaving chemotherapy as the main option for treatment. However, response to chemotherapy varies, and the presence of even a small number of unresponsive tumour cells can cause the disease to recur. With his second MSFHR award, Timon Buys is continuing his research on identifying genetic alterations in lung cancer tumours. He is working to identify genomic “signatures” that might predict how effective a drug will be in treating a given tumour. Using “array comparative genomic hybridization” — a technology that allows researchers to assess cancer-associated gene alterations throughout the whole human genome — Buys will characterize the genetic changes in lung tumour tissue that has been isolated from patients before and after treatment. He will use this data to determine whether mis-regulation of specific genes is associated with a patient’s response to different types of chemotherapy treatments, essentially identifying those genes that play a role in resisting drug activity. As resistance genes are identified, treatment strategies can be tailored so that they will be most effective for a specific tumor. This approach to “personalized medicine” – matching treatments to the genetic make-up of individual tumors – may greatly improve patient survival rates.
Modulating proteolysis in Huntington disease: Eluding the toxic fragment
Huntington’s disease is an inherited neurodegenerative disorder primarily caused by the early death of brain cells. The disease typically begins with mental and emotional disturbances, which progress to involuntary, jerky movements. An abnormal form of the Huntingtin protein is associated with Huntington’s disease. Huntingtin is made of 3144 amino acids, or molecular building blocks. In a landmark study, after mutating just one of those building blocks, genetically modified caspase-resistant mice (those resistant to intracellular proteins that lead to cell disintegration) were completely protected from all symptoms of Huntington’s disease. Jeffrey Carroll’s research aims to find medical interventions beyond genetic modification that produce the same effect. He is developing tools to quickly analyze the effectiveness of drugs at inhibiting cell disintegration. He has designed and is building a cell-based system that allows him to screen libraries of hundreds of thousands of drugs that might offer some protection. Carroll is also investigating a protein-cutting enzyme, caspase-2, who’s activity is dramatically reduced in caspase-resistant mice. Carroll aims to increase understanding of the pathway between Huntingtin and caspase-2. Findings could contribute to therapies for Huntington’s disease.
The role of Notch in Endothelial Cell Survival and Apoptosis
Cardiovascular disease is a leading cause of death worldwide. Some people are born with a heart defect, while others develop atherosclerosis — a build up of waxy plaque in the blood vessels which results in the narrowing of the arteries, increasing the risk of heart attack and stroke. The thin layer of cells that line the blood vessels and heart chamber are called endothelial cells. These cells are vulnerable to injury and/or death due to the constant exposure to injurious agents in the blood such as bacterial and viral particles, homocysteine — an amino acid associated with heart disease, and high blood glucose resulting from diabetes. It is when these endothelial cells become injured or die, that cardiovascular disease occurs or worsens. Continuing the work she began with her MSFHR-funded Master’s research, Linda Ya-ting Chang is studying the function of a particular family of proteins called Notch, in the survival of endothelial cells. Two proteins known to protect against death in other cells show increased activity when Notch is present. Chang is investigating whether the same protection is seen with endothelial cells, and how Notch proteins increase the rate of cell survival. The long-term goal is to identify molecules that protect endothelial cells from injury, lessening the progression of atherosclerosis and congenital heart disease, and potentially reducing the risk of heart attack and stroke.
Discovery of novel biomarkers in lung cancer using an integrative genomics approach
Even though it is the most preventable of all cancers, lung cancer is the leading cause of cancer death for both men and women. The incidence continues to climb among women while decreasing among men. About 23,300 Canadians will be diagnosed with lung cancer in 2007, and 19,900 will die of the disease. Although studies have identified genetic differences in lung cancer, genetic targets for cancer diagnosis and treatment have not yet proven effective. Rajagopal (Raj) Chari is conducting a study to examine the full range of genetic and non-genetic mechanisms that affect the DNA and give rise to huge diversity among individual lung tumours. Chari wants to identify common functional disruptions based on these differing mechanisms, with the goal of determining which changes in key genes cause tumour growth. These genes should provide effective biomarkers for diagnosing and treating lung cancer, leading to more personalized medicine targeting the individual differences in tumours.
Investigation of the molecular mechanisms of inactivation of the voltage-gated potassium channels Kv1.5 and Kv4.2
The strict regulation of our heart rates allows our bodies to adapt to changing conditions to provide the different parts of our bodies with the appropriate amounts of oxygen and nutrients. Cardiac arrhythmias, or irregularities in the heart rate, can have devastating consequences such as heart attack or stroke. Understanding the basis for heart rate regulation may improve our current ability to treat and prevent cardiac arrhythmias. Voltage-gated potassium (Kv) channels are proteins in the heart tissue that play a critical role in the regulation of heart rate. Kv channels open and close depending on the electrical activity with in the heart. By allowing potassium ions to exit the heart muscle cells, Kv channels indirectly regulate whether the cells (and hence heart) will contract, or beat. After the channels open, they often undergo a process known as inactivation which causes the channel to close and prevents potassium flow. The rate at which channels enter and exit inactivation plays an important role in determining heart rate. May Cheng is studying the inactivation properties of two Kv channels found in the heart, Kv1.5 and Kv4.2. Kv1.5 has been implicated in atrial fibrillation, and Kv4.2 is believed to play a role in ventricular fibrillation. By increasing our understanding of the basic processes behind potassium channel inactivation, this research may lead to future therapies to treat cardiac arrhythmias.